Normal glucose tolerance is maintained by a balance between insulin secretion and insulin action to enhance glucose disposal and regulate glucose output. In normal individuals basal and postprandial insulinemia increases so that glycemia does not exceed the normal range at basal and with meals. This compensation is due to upregulation of 13-cell sensitivity to secretagogues, as well as downregulation of first-pass liver insulin clearance. Impaired glucose tolerance results when there is inadequate compensation for insulin resistance, and as this dysfunction progresses, diabetes develops. The precise mechanisms by which resistance results in 13-cellupregulation are not known. We are examining several mechanisms which may play a role in hyperinsulinemic compensation for insulin resistance. We exploit the isocaloric or hypercaloric fat-fed dog model, which develops visceral adiposity, insulin resistance and a well-defined pattern of compensation. We will determine whether postprandial or nocturnal glucose or free fatty acids explain upregulation of p-cell function. We will counter increases in postprandial nutrients with pharmacological agents (acarbose and/or metformin). We examine the relationship between cortisol and growth hormone and metabolic compensation, and disrupt the secretion/action of these hormones with antagonists infused systemically or into the third ventricle of the brain. We consider whether gastrointestinal peptide GLP-1 is an important mediator of the compensatory response to insulin resistance. We hypothesize that GLP-1 is stimulated in the fat-fed model and acts via specific receptors in the portal vein. The putative GLP-1 reflex will be blocked by denervation of the portal vein, or with portal infusion of GLP- 1 antagonists. We will examine whether portal GLP-1 plays a vital role in the putative action of the peptide to upregulate islets in the insulin resistant state. Failure of "compensatrins" to upregulate may be the earliest change in the pathogenesis of Type 2 diabetes. Identification of the origin and metabolic actions of such molecules should lead to more accurate identification of those at risk for diabetes, and allow for prevention of the disease.